T cell development and activation are dependent on multiple independent signaling pathways. These include signals through T cell antigen receptors (TCRs), co-receptors, co-stimulatory receptors, cytokine receptors, adhesion molecules, and others. As tyrosine kinases are known to play a critical role in receptor proximal signaling events, we set out to identify novel tyrosine kinases expressed in T cells. This effort led to the cloning of Jak3, which was shown to be critical for signaling through gammac-containing cytokine receptors, including the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. To examine the role of Jak3 during lymphocyte development and activation, we generated Jak3-deficient mice, and have shown that T cell maturation and function are grossly aberrant in these mice. The importance of Jak3 in the immune system is also highlighted by the identification of human severe combined immunodeficiency patients whose disease is caused by mutations in the Jak3 gene. We propose to use the Jak3-deficient mice as a model system to investigate the precise role of Jak3 in the immune system. First, we will test the hypothesis that Jak3 plays a critical role in the development and/or survival of T cell progenitors in the thymus, fetal liver, or bone marrow. We will also examine the role of Jak3 in mature peripheral T cells, and test the idea that Jak3 is necessary for long-term T cell survival, responsiveness to antigenic stimulation, and activation-induced cell death. Finally, we will use a gene-targeting "knock-in" strategy to perform structure/function analysis of Jak3 in vivo, allowing us to assess the activity of specific Jak3 mutants in primary cells. As tyrosine kinases have been implicated in numerous human immunodeficiency diseases and cancers, and are involved in decisions leading to proliferation versus differentiation in many cell lineages, these experiments will provide information relevant to an understanding of oncogenesis, autoimmunity, as well as genetic immunodeficiencies.